Relationship between Activin A, anti-angiogenic factors and inflammatory cytokines in the pathogenesis of preeclampsia. (#110)

Background:
Preeclampsia is a pregnancy-specific disorder that continues to cause
significant maternal and fetal morbidity and mortality due to our lack of
understanding of its pathophysiology. Current evidence indicates that an
increase in inflammatory cytokines, such as TNF-a and IL-6, resulting from placental oxidative stress
stimulates placental production of the anti-angiogenic factors, sFlt1 and sEng.
Recently, our group has shown that Activin A also plays a role in disease
development as pregnant mice treated with Activin A develop preeclampsia-like
symptoms. However, the relationship between Activin A and the other key factors
in the development of preeclampsia is unknown. Aim: to determine the relationship between Activin A, anti-angiogenic
factors and inflammatory cytokines. Hypothesis: TNF-a and IL-6 stimulates placental Activin A
production, which in turn stimulates the placental production of sFlt1 and sEng
in the pathophysiology of preeclampsia. Methods: Placental explants from
healthy term pregnancies were cultured with either Xanthine/ Xanthine oxidase
(X/XO), TNF-a,
IL-6 or sFlt1 and sEng, and Activin A production was determined by ELISA and
qPCR. sFlt1 and sEng production was also determined by ELISA in explants
treated with Activin A. Results: Placental
explants treated with X/XO showed a 3-fold increase in Activin A production
(P<0.05). Explants treated with IL-6 also showed a similar 3-fold increase
in placental Activin A production (P<0.05). However, sFlt1 and sEng
treatment did not affect Activin A production by the placental explants
(P>0.05). The production of sFlt1 and sEng by the explants were also not
affected by Activin A treatment (P>0.05). Conclusion: These results suggest that during the development of
preeclampsia, an increase in inflammatory cytokines, such as IL-6, resulting
from placental oxidative stress stimulates the placental production of
anti-angiogenic factors and Activin A independent of each other. Therefore,
inhibition of the anti-angiogenic factors alone may not be a sufficient
therapeutic strategy for preeclampsia.